tbuckley/cabot-search huggingface dataset:
P896: DEVELOPMENT AND VALIDATION OF A FRAILTY PREDICTION MODEL MORE SUITABLE FOR MULTIPLE MYELOMA IN CHINESE PATIENTS: THE TM FRAILTY SCORE.
Authors: Y. Chen, J. Gu, B. Huang, J. Liu, X. Li, J. Li
Journal: HemaSphere (2022)

Background: Frailty is associated with adverse clinical outcomes in patients with multiple myeloma (MM). Accurate evaluation of frailty is critical when choosing appropriate chemotherapy regimens for elderly patients. Currently, the IMWG geriatric assessment (GA) is widely used to assess tolerance to chemotherapy for elderly patients. However, the applicability of the IMWG GA in the Chinese MM population is limited. Aims: To developed a new frailty model that is more suitable for Chinese patients with MM. Methods: The applicability of the IMWG GA was evaluated in 167 consecutive patients diagnosed with MM from June 2019 to September 2021 at the First Affiliated Hospital of Sun Yat-sen University. Eight comprehensive geriatric assessment (CGA) domains were analyzed in 135 of these patients to screen items most closely associated with the outcomes, including grade ≥ 3 adverse events (AEs), treatment discontinuation, TTP, and OS. A new frailty prediction model was developed, and its fitness and predictive performance were compared to those of the IMWG GA. Results: The patients in the IMWG GA Frail group had a higher rate of grade ≥3 AEs, a higher rate of treatment discontinuation, and a greater risk of death than those in the Fit group (P<0.05). No significant differences were observed in patients in the Int-fit group who experienced chemotherapy AEs, treatment discontinuation, and TTP compared with the Fit group. By screening items in all 8 CGA domains, multivariate analysis confirmed that the Timed Up and Go test（TUG） and the Mini Nutritional Assessment Short-Form（MNA-SF） were independent prognostic factors for grade ≥3 AEs and OS. We found that the TUG and MNA-SF scores could stratify the risk of grade ≥ 3 AEs in the IMWG GA Int-fit group (P < 0.05). After MNA-SF was added to construct the IMWG GA Plus model, Harrell’s concordance index (C-index) of the IMWG GA Plus model for the prediction of grade ≥3 AEs increased from 0.662 to 0.701. The C-index for treatment discontinuation rose from 0.636 to 0.669. We further combined the TUG test and the MNA-SF to construct the TM frailty scoring system. The KM curve analysis showed that the TM frailty score could well distinguish the risk of AEs between the Fit and Frail groups (P<0.05). The C-index of the TM frailty score was 0.741, 0.690, and 0.702 for grade ≥ 3 AEs, treatment discontinuation, and OS, respectively, suggesting good predictive ability, which was higher than that of the IWMG GA (C-index=0.662, 0.636 and 0.631, respectively) and the IMWG GA Plus model (C-index=0.701, 0.656 and 0.618, respectively). Image:Summary/Conclusion: A novel scoring system—the TM frailty score—was developed by combining the TUG (T) and MNA-SF (M). The TM frailty score is more appropriate than the IMWG GA for evaluating frailty in the Chinese population.
Hollow microneedle assisted intradermal delivery of hypericin lipid nanocapsules with light enabled photodynamic therapy against skin cancer
Authors: Heba Abd-El-Azim, Ismaiel A. Tekko, Ahlam Ali, Alyaa Ramadan, Noha Nafee, Nawal Khalafallah, Taifur Rahman, William Mcdaid, Rania G. Aly, Lalitkumar K. Vora, Steven J. Bell, Fiona Furlong, Helen O. McCarthy, Ryan F. Donnelly
Journal: Journal of Controlled Release (2022)

Photodynamic therapy (PDT) to manage non-melanoma skin cancers has garnered great attention over the past few years. Hypericin (Hy) is a potent lipid-soluble photosensitiser with promising anticancer therapeutic activities. Nevertheless, its poor water-solubility, aggregation in biological systems and insufficient skin penetration restricted its effective exploitation. Herein, we report for the first-time encapsulation of Hy into lipid nanocapsules (Hy-LNCs), and then application of an AdminPen™ hollow microneedles (Ho-MNs) array and an in-house fabricated Ho-MN to enable efficient intradermal delivery. The physicochemical properties, photoactivity, ex vivo drug distribution and cellular uptake were evaluated. Results showed that Hy-LNCs were successfully formed with a particle size of 47.76 ± 0.49 nm, PDI of 0.12 ± 0.02, high encapsulation efficiency (99.67% ± 0.35), 396 fold higher photoactivity, 7 fold higher skin drug deposition, significantly greater cellular uptake and higher photocytotoxicity compared to free Hy. The therapeutic effect of Hy-LNCs was finally assessed in vivo using a nude mouse model with transplanted tumours. Interestingly, Hy-LNCs delivered by Ho-MN exhibited remarkable anti-tumour destruction (85.84%) after irradiation with 595 nm. This study showed that Ho-MNs-driven delivery of Hy-LNCs followed by irradiation could form a promising minimally invasive, effective and site-specific approach for managing non-melanoma skin cancers.
Quantitative Proteomics in Translational Absorption, Distribution, Metabolism, and Excretion and Precision Medicine
Authors: Deepak Ahire, Laken Kruger, Sheena Sharma, Vijaya Saradhi Mettu, Abdul Basit, Bhagwat Prasad
Journal: Pharmacological Reviews (2022)

A reliable translation of in vitro and preclinical data on drug absorption, distribution, metabolism, and excretion (ADME) to humans is important for safe and effective drug development. Precision medicine that is expected to provide the right clinical dose for the right patient at the right time requires a comprehensive understanding of population factors affecting drug disposition and response. Characterization of drug-metabolizing enzymes and transporters for the protein abundance and their interindividual as well as differential tissue and cross-species variabilities is important for translational ADME and precision medicine. This review first provides a brief overview of quantitative proteomics principles including liquid chromatography-tandem mass spectrometry tools, data acquisition approaches, proteomics sample preparation techniques, and quality controls for ensuring rigor and reproducibility in protein quantification data. Then, potential applications of quantitative proteomics in the translation of in vitro and preclinical data as well as prediction of interindividual variability are discussed in detail with tabulated examples. The applications of quantitative proteomics data in physiologically based pharmacokinetic modeling for ADME prediction are discussed with representative case examples. Finally, various considerations for reliable quantitative proteomics analysis for translational ADME and precision medicine and the future directions are discussed. SIGNIFICANCE STATEMENT: Quantitative proteomics analysis of drug-metabolizing enzymes and transporters in humans and preclinical species provides key physiological information that assists in the translation of in vitro and preclinical data to humans. This review provides the principles and applications of quantitative proteomics in characterizing in vitro, ex vivo, and preclinical models for translational research and interindividual variability prediction. Integration of these data into physiologically based pharmacokinetic modeling is proving to be critical for safe, effective, timely, and cost-effective drug development.
P488: THZ1, A COVALENT CDK7 INHIBITOR, INDUCES APOPTOSIS IN ACUTE MYELOID LEUKEMIA CELLS AND EXERTS SYNERGISTIC ANTILEUKEMIA ACTIVITY WITH AZACITIDINE
Authors: S. Zhang, H. Liu
Journal: HemaSphere (2022)

Background: Acute myeloid leukemia (AML) is a malignant blood cancer that develops mainly in elderly adults and has dismal clinical outcomes. Azacitidine (AZA) is still the preferred treatment for elderly patients unfit for intensive chemotherapy. However, the remission rate of azacitidine monotherapy is dismal, which necessitates the multidrug combination therapy. THZ1, a CDK7 inhibitor, has been proven to be effective in various cancers by regulating transcription and the cell cycle and inducing cell death. Here, we investigated the antitumor effect of THZ1 monotherapy and its combination treatment with AZA. Aims: To investigate the antitumor activity of the CDK7 inhibitor - THZ1 in acute myeloid leukemia (AML). Methods: We first examined the cell viability of THZ1 against THP-1, MOLM-13, OCI-AML3 cell lines using CCK-8 assays. We used flow cytometry to detect apoptosis after cells were stained with Annexin V-FITC/Propidium Iodide (PI), and western blot to detect the expression levels of proteins. We detect cell cycle by flow cytometry after cells were stained with 50 µg/ml PI and then analyzed with ModFit LT 5.0. RNA-sequencing analysis was performed to explore the potential mechanism of THZ1 in AML cells. In the double-drug combination experiment, we used CCK-8 assays to detect the effect of drugs on the viability of the three cell lines, used CompuSyn software to calculate the combination index (CI), which indicates additive effects (CI = 1.0), synergism (CI < 1.0), and antagonism (CI > 1.0). Results: THZ1 decreased viability and induced apoptosis in THP1, MOLM-13, and OCI-AML3 cells in a dose- and time-dependent manner. Besides, THZ1 inhibited phosphorylation of Ser2, Ser5, and Ser7 residues of RNA Pol II CTD and induced cell cycle arrest at G0/G1 phase in AML cells. RNA-sequencing analysis revealed that THZ1 induced changes in the expression of genes involved in apoptosis, the cell cycle, and DNA repair. Combined treatment with AZA and THZ1 showed a synergetic effect (CI < 1.0). Western blot analysis of apoptosis markers, including cleaved caspase3 and PARP1, demonstrated that THZ1 increased the expression of these markers and potentiated AZA-related apoptosis. Compared with monotherapy, combined treatment with AZA and THZ1 resulted in more Annexin V positive cells detected by flow cytometry, which further verified the synergistic effect of the two drugs. Western blot results indicate that combined treatment with AZA and THZ1 downregulates MCL1 at the protein level without an apparent decrease in BCL2 protein expression. Image:Summary/Conclusion: Our data demonstrate that the CDK7 inhibitor THZ1 induces the apoptosis of AML cells and exerts synergistic antileukemia activity with azacytidine, which provide the rationale for combination treatment with AZA and THZ1 for AML.
Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis
Authors: Kangkang Ying, Yifeng Zhu, Jianqin Wan, Chenyue Zhan, Yuchen Wang, Binbin Xie, Peirong Xu, Hongming Pan, Hangxiang Wang
Journal: Bioactive Materials (2022)

The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases. Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment. However, only a limited number of nanotherapies have enter clinical trials or are clinically approved. Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system (MPS), resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors. Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy. Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages. Polymer conjugation revived the parent camptothecin agent (e.g., 7-ethyl-10-hydroxy-camptothecin), enabling lipid nanoparticle encapsulation. Furthermore, macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin, increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy. When tested in a preclinical murine model of breast cancer, macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles. Furthermore, intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity. Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity. This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers.
P408: NRAS MUTATIONS ARE INVOLVED IN ACUTE MYELOID LEUKAEMIA DRUG RESISTANCE
Authors: F. Healy, V. Marensi, J. Woolley, D. MacEwan
Journal: HemaSphere (2022)

Background: Acute Myeloid Leukaemia is the most common adult leukaemia, typically associated with poor prognosis. While rates of response to initial cytarabine-based induction chemotherapy are high, the majority of patients will relapse even with haematopoietic stem cell transplant. Thus, the addition of targeted therapies to induction regimens are becoming more widespread, particularly the use of midostaurin and gilteritinib. Even so, resistance is emerging to FLT3 inhibitors, and can often be attributed to NRAS mutations. Aims: Here, we use over-expression and CRISPR-Cas9 to assess the involvement of NRAS mutations in FLT3-inhibitor resistance cell line models (MOLM-13, FLT3-ITD heterozygous and MV4-11, FLT3-ITD homozygous) that had been previously generated in our lab. Methods: Drug sensitivity was determined by quantification of apoptosis 72 hours post-treatment (Annexin-V/Propidium Iodide staining). NRAS mutational hotspots associated with increased activation and drug resistance were analysed by Sanger Sequencing. NRAS over-expression and knock-out cell lines were generated using either transfection (HEK293T) or lentiviral transduction (MOLM-13 and MV4-11). Signalling dynamics driving resistance were determined by immunoblotting. Results: Mutations arose in the MOLM-13-resistant and MV4-11 resistant cell lines at common NRAS mutational hotspots (Q61 and G12, respectively). NRAS Q61K over-expression in the parental MOLM-13 cell line decreased sensitivity to the FLT3 inhibitors gilteritinib, quizartinib, as well as cytarabine, relative to the parental cell line. However, they remained more sensitive to FLT3 inhibition and cytarabine than the resistant cells. In contrast, NRAS-Q61K over-expression caused ~3-fold decrease in sensitivity to trametinib, the MEK inhibitor that acts downstream of NRAS, relative to both the MOLM-13 and MOLM-13-resistant cell lines (Table 1). MOLM-13-NRAS-Q61K over-expression cells showed a growth advantage compared to parental cells in normal culture. In MV4-11-NRAS-Q61K cells, preliminary mechanistic analysis has shown a decrease in ERK phosphorylation. Conversely, CRISPR-Cas9-mediated NRAS knockout in HEK293T appeared to increase ERK activity. Image:Summary/Conclusion:NRAS mutations contribute to a FLT3-inhibitor-resistant phenotype, confer a growth advantage in FLT3-ITD+ AML and may act independently of ERK. We have engineered the MOLM-13-resistant and MV4-11-resistant cell lines to express Cas9 under a doxycycline-inducible promoter, to permit stable reversion of the respective mutations. Future work will use these cells to create a CRISPR-mediated reversion of the NRAS mutations which have arisen in the resistant cell lines, to better understand the role of NRAS mutations in FLT3-ITD+ AML. We will better characterise the impacts of a host of NRAS mutations within AML using over-expression and knockout cell lines, and assess drug sensitivity and subsequent pathway re-wiring.
Racial and Ethnic Disparities in Postpartum Care in the Greater Boston Area During the COVID-19 Pandemic
Authors: Tianyue Mi, Peiyin Hung, Xiaoming Li, Alecia McGregor, Jingui He, Jie Zhou
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Racial and ethnic disparities in postpartum care access have been well identified in the United States. Such disparities could be exacerbated by the COVID-19 pandemic because of amplified economic distress and compromised social capital among pregnant women who belong to racial or ethnic minority groups. <h3>Objective</h3> To examine whether the COVID-19 pandemic is associated with an increase in the existing racial and ethnic disparity in postpartum care access. <h3>Design, Setting, and Participants</h3> This was a retrospective cohort study using electronic health records data. Multinomial logistic regressions in an interrupted time series approach were used to assess monthly changes in postpartum care access across Asian, Hispanic, non-Hispanic Black (hereafter, Black), non-Hispanic White (hereafter, White) women, and women of other racial groups, controlling for maternal demographic and clinical characteristics. Eligible participants were women who gave live birth at 8 hospitals in the greater Boston, Massachusetts, area from January 1, 2019, to November 30, 2021, allowing for tracking 90-day postpartum access until March 1, 2022. <h3>Exposures</h3> Delivery period: prepandemic (January to December 2019), early pandemic (January to March 2020), and late pandemic (April 2020 to November 2021). <h3>Main Outcomes and Measures</h3> Postpartum care within 90 days after childbirth was categorized into 3 groups: attended, canceled, and nonscheduled. <h3>Results</h3> A total of 45 588 women were included. Participants were racially and ethnically diverse (4735 [10.4%] Asian women, 3399 [7.5%] Black women, 6950 [15.2%] Hispanic women, 28 529 [62.6%] White women, and 1269 [2.8%] women of other race or ethnicity). The majority were between 25 and 34 years of age and married and had a full-term pregnancy, vaginal delivery, and no clinical conditions. In the prepandemic period, the overall postpartum care attendance rate was 75.2%, dropping to 41.7% during the early pandemic period, and rebounding back to 60.9% in the late pandemic period. During the months in the late pandemic, the probability of not scheduling postpartum care among Black (average marginal effect [AME], 1.1; 95% CI, 0.6-1.6) and Hispanic women (AME, 1.3; 95% CI, 0.9-1.6) increased more than among their White counterparts. <h3>Conclusions and Relevance</h3> In this cohort study of postpartum care access before and during the COVID-19 pandemic, racial and ethnic disparities in postpartum care were exacerbated following the onset of the COVID-19 pandemic, when postpartum care access recovered more slowly among Black and Hispanic women than White women. These disparities require swift attention and amelioration to address barriers for these women to obtain much needed postpartum care during this pandemic.
Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia
Authors: Robin Foà, Sabina Chiaretti
Journal: New England Journal of Medicine (2022)

Until recently, Ph-positive ALL was very aggressive and difficult to treat. Current frontline therapy, based on tyrosine kinase inhibitors, glucocorticoids, and blinatumomab, has increased survival, with high-level clearance of measurable tumor cells.
P585: VENETOCLAX IN COMBINATION WITH INTENSIVE TREATMENT PROTOCOLS FOR PATIENTS WITH HIGH-RISK ACUTE MYELOID LEUKEMIA – A MULTICENTER REAL-WORLD ANALYSIS
Authors: O. Wolach, A. Frisch, L. Shargian, M. Yeshurun, A. Apel, V. Vainstein, Y. Moshe, S. Shimony, O. Amit, Y. Bar On, Y. Ofran, P. Raanani, B. Nachmias, R. Ram
Journal: HemaSphere (2022)

Background: The addition of venetoclax, a selective BCL2-inhibitor, to low intensity therapies was shown to improve the survival of patients with acute myeloid leukemia (AML) that are ineligible for intensive induction chemotherapy. Based on the encouraging anti-leukaemic properties of venetoclax and safety profile, several studies are currently exploring venetoclax in combination with high-intensity chemotherapy in high-risk AML scenarios such as ELN adverse-risk AML and in relapsed and refractoy (R/R) AML. The addition of venetoclax to established intensive chemotherapy protocols in these trials are generally reported to be associated with enhanced efficacy, frequently at the cost of significant hematological and infectious toxicities that requires dose modifications of both chemotherapy and venetoclax dosing Aims: To assess the safety and efficacy of venetoclax in combination with intensive treatment protocols in a ‘real-world’ setting. Methods: A multicenter retrospective cohort study in six academic centers in Israel. The decision to treat a patient with venetoclax in addition to an intensive treatment protocol as well as the choice of protocol and dosing were at discretion of the treating physician. Results: Twenty-nine patients were included in analysis (median age 53.4 years). Most patients were treated for R/R AML (n=27, 93%) with a median of one (0-5) previous lines of therapy and 48% of patients (n=14) having prior allogeneic hematopoietic-cell transplantation (HCT). Most patients were treated with venetoclax in combination with FLAG-IDA protocol (n=25, 86%). Median follow-up was 6.3 (0.7-23.7) months. Platelet and neutrophil recovery were observed at a median of 31 (95%CI 17.6-38.3) and 24 (95%CI 20-28) days, respectively. Infectious complications were common (blood stream infections, 41% and invasive fungal infections, 28%) and 30-day mortality was 14%. Composite complete remission (CRc) was 72% for the entire cohort and 91% in patients treated for post-HCT relapse. Incidences of relapse-free and overall survival at 12 months were 90% (95% CI 76%-98%) and 55% (95% CI 21%-63%), respectively. Image:Summary/Conclusion: The addition of venetoclax to intensive therapy is effective in high-risk AML, especially in post-HCT relapse setting. Prophylaxis and surveillance for infections are crucial.
Antigenic cartography of SARS-CoV-2 reveals that Omicron BA.1 and BA.2 are antigenically distinct
Authors: Anna Z. Mykytyn, Melanie Rissmann, Adinda Kok, Miruna E. Rosu, Debby Schipper, Tim I. Breugem, Petra B. van den Doel, Felicity Chandler, Theo Bestebroer, Maurice de Wit, Martin E. van Royen, Richard Molenkamp, Bas B. Oude Munnink, Rory D. de Vries, Corine GeurtsvanKessel, Derek J. Smith, Marion P. G. Koopmans, Barry Rockx, Mart M. Lamers, Ron A. M. Fouchier, Bart L. Haagmans
Journal: Science Immunology (2022)

The emergence and rapid spread of SARS-CoV-2 variants may affect vaccine efficacy substantially. The Omicron variant termed BA.2, which differs substantially from BA.1 based on genetic sequence, is currently replacing BA.1 in several countries, but its antigenic characteristics have not yet been assessed. Here, we used antigenic cartography to quantify and visualize antigenic differences between early SARS-CoV-2 variants (614G, Alpha, Beta, Gamma, Zeta, Delta, and Mu) using hamster antisera obtained after primary infection. We first verified that the choice of the cell line for the neutralization assay did not affect the topology of the map substantially. Antigenic maps generated using pseudo-typed SARS-CoV-2 on the widely used VeroE6 cell line and the human airway cell line Calu-3 generated similar maps. Maps made using authentic SARS-CoV-2 on Calu-3 cells also closely resembled those generated with pseudo-typed viruses. The antigenic maps revealed a central cluster of SARS-CoV-2 variants, which grouped on the basis of mutual spike mutations. Whereas these early variants are antigenically similar, clustering relatively close to each other in antigenic space, Omicron BA.1 and BA.2 have evolved as two distinct antigenic outliers. Our data show that BA.1 and BA.2 both escape vaccine-induced antibody responses as a result of different antigenic characteristics. Thus, antigenic cartography could be used to assess antigenic properties of future SARS-CoV-2 variants of concern that emerge and to decide on the composition of novel spike-based (booster) vaccines.